Deficiencies in choroidal blood flow (ChBF) have long been suggested to underlie age-related retinal decline, and cause the outer retinal abnormalities that set the stage for the inflammatory cascade leading to AMD. Nonetheless, experimental evidence that this is the case has been lacking. We have been investigating both the parasympathetic and sympathetic control of ChBF, and found that the vasodilatory parasympathetic input helps maintain basal ChBF during low systemic blood pressure (BP), while the vasoconstrictory sympathetic input helps maintain basal ChBF during high systemic BP. We have found that this adaptive control, which we term ChBF baroregulation, is impaired by age, and when impaired by experimental manipulations leads to declines in retinal function. The studies proposed here will build on these findings and experimentally determine if impaired neurogenic ChBF baroregulation in the long term leads to the types of outer retinal pathologies that characterize early AMD progression. Three Aims will be pursued. In the first Aim, we will determine the impact of disrupted parasympathetic and/or disrupted sympathetic regulation of ChBF on retinal health and function in rats housed in normal diurnal light. Whole- field scotopic ERG, visual acuity, and contrast sensitivity will be determined at 6 and 12 months post lesion. Choroidal baroregulatory defects will be assessed at the same time points, and animals then sacrificed for morphological and neurochemical analysis of outer retina at these same time points. In the morphological and neurochemical analysis, we will quantify photoreceptor and RPE cell loss, RPE-Bruch's membrane interface pathologies, and the accumulation of oxidized protein, lipid waste and inflammatory proteins typical of AMD progression. We will also determine if choroidal vessel attenuation and pericyte loss are a long-term consequence of disrupted parasympathetic and/or sympathetic control of ChBF. In our second Aim, we will determine if neurogenic ChBF baroregulation and autonomic innervation are prematurely impaired in complement factor H (CFH) - deficient mice, which show progressive outer retinal and choriocapillaris pathology resembling that in AMD. CFH normally inhibits the alternative complement pathway, and polymorphisms that reduce protein function are AMD risk factors in humans. Assessments of retinal function (ERG, visual acuity and contrast sensitivity) and morphological and neurochemical analyses of outer retina and choroid, as in Aim 1, will be performed in these mice in separate cohorts at 4, 8 and 12 months of age. In the third Aim, we will use immunolabeling to assess the association between outer retinal AMD pathology and loss of innervation of choroid, and the relation of AMD risk genes to innervation loss. Our studies may lead to testing of adaptive regulation of choroidal blood flow (especially in response to blood pressure fluctuations) as an AMD risk assessment, as well as lead to use of drugs that improve neural regulation of choroidal blood flow to slow AMD onset and progression.